Project Summary: We have generated a mouse knockout (KO) of the regulator of G protein signaling 14 (RGS14). The RGS14 KO mice live longer than their wild type (WT) littermates and are protected against stress, type 2 diabetes and obesity, all features related to cardiovascular risk protection. The mechanisms mediating these salutary effects of the RGS14 KO involve the striated muscle. The RGS14 KO also has increased brown adipose tissue, which is likely involved in the mechanism of its protective effects. The goal of this proposal is to determine the mechanisms mediating these salutary actions. We plan to establish the RGS14 KO as a novel model for longevity and determine to what extent striated muscle specific loss of RGS 14 and brown adipose tissue contribute to longevity, and protection against obesity and diabetes. In this proposal ?diabetes? is used to reflect protection of glucose utilization and insulin resistance, rather than the clinical disease. Our long term goal is to develop a clinically useful pharmacological inhibitor of RGS14. The proposal is based on the following hypotheses: Hypothesis A: Striated muscle specificity of RGS14 KO protects against the development of insulin resistance, glucose intolerance and obesity and extends lifespan mediated by increased energy metabolism through mitochondrial oxidation and protection against oxidative stress through the NAD+/SIRT3/MnSOD pathway. Hypothesis B: The RGS14 KO has the additional novel feature of increased brown adipose tissue, which also protects against diabetes, obesity and prolongs lifespan.